Compounds designed based on artificial intelligence for treating alzheimer's disease, and preparation method and medical use thereof

Abstract

The present application provides a compound for treating Alzheimer's disease designed based on artificial intelligence, a preparation method and medical uses thereof. The compound is shown as formula I. Through pharmacological experiments, it is found that compounds 548 and 398 both have the effect of inhibiting LPS-induced neuroinflammation, in addition, compound 548 can improve LPS lateral ventricle injection mouse neuroinflammation, improve Aβ 1‑42 Lateral ventricle injection mouse neuroinflammatory injury, so the compound shown as formula I can be used for preparing a drug for treating Alzheimer's disease.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and specifically relates to a compound for treating Alzheimer's disease designed based on artificial intelligence and a preparation method and medical use thereof, and more particularly to a (hydroxyphenylethyl) phenolic compound and a preparation method and application thereof in preparing a medicament for treating Alzheimer's disease. BACKGROUND

[0002] According to statistics, the number of patients with Alzheimer's disease worldwide has reached 500 million in 2018, and is expected to increase to 150 million by 2050. It can be seen that Alzheimer's disease will become a huge burden on the world economy in the future. The pathological mechanism of Alzheimer's disease is complex. Studies have shown that Alzheimer's patients generally have a large number of β-amyloid protein deposits in the extracellular brain nerve cells, neurofibrillary tangles formed by abnormal phosphorylation of tau protein, neuron loss, and neuroinflammation. The clinical treatment of Alzheimer's disease mainly uses acetylcholinesterase inhibitors and N-methyl D-aspartate receptor antagonists, but the efficacy is poor and adverse reactions are easy to occur. Therefore, it is of great significance to develop drugs against Alzheimer's disease.

[0003] The complexity of the pathogenesis of Alzheimer's disease poses a challenge to the development of drugs to reverse the condition of Alzheimer's disease. Investigations have shown that the cost of Alzheimer's disease worldwide will reach 2.54 trillion US dollars by 2030, and pharmaceutical companies around the world have been investing a lot of manpower and resources in the development of drugs to reverse the condition of Alzheimer's disease. Pharmaceutical companies such as Pfizer, Merck, and Johnson & Johnson have tried to develop various drugs to treat Alzheimer's disease, but all have failed in the clinical stage. With the development of artificial intelligence technology, this technology is expected to empower the entire process of anti-Alzheimer's drug discovery.

[0004] As a rapidly developing discipline, artificial intelligence aims to build a technology that simulates human thinking and solves real-world problems. In the field of artificial intelligence, machine learning and deep learning have great potential in drug development. Machine learning is widely used in classification and regression prediction in the field of new drug development. Deep learning overcomes the limitations of machine learning, which must predefine recognition features and is based on template matching, simulates the human brain neural network, learns from a large amount of uncategorized and unlabeled raw data, and extracts effective information by itself. With the improvement of computer performance and the accumulation of data, deep learning is increasingly applied in new drug development. Variational Auto-Encoder (VAE) is an algorithm of deep learning. In 2016, Gomez-Bombarelli et al. developed an automatic chemical molecule design system ChemVAE based on VAE. Since then, VAE models have been widely used in the generation of new molecules. SUMMARY

[0005] In view of the above, the present application designs a new molecule generation model based on VAE and designs two small molecule compounds 548 and 398 with anti-Alzheimer's activity using the model, synthesizes and evaluates the therapeutic effect of the compounds on Alzheimer's disease.

[0006] One of the objects of the present application is to provide a compound represented by Formula I:

[0007]

[0008] In Formula I, R1 represents a substituent on a benzene ring, which can be mono-substituted or multi-substituted,

[0009] When R1 is mono-substituted, R1 represents C1-C6 alkyl, specifically ethyl or propyl;

[0010] When R1 is multi-substituted, R1 each independently represents C1-C6 alkyl, specifically ethyl or propyl. In an embodiment of the present application, the compound represented by Formula I is any one of the following compounds:

[0011]

[0012] The compound 548 is prepared by the following reaction equation through a method comprising the following steps:

[0013]

[0014] Reagents and conditions: (a) NBS, AIBN, DCE, 80 °C, 8 h, 90%; (b) PPh3, CH3CH, reflux, 8 h, 89%; (c) anisaldehyde, LiOH, IPA, 60 °C, overnight, 75%; (d) trimethylsilyl acetylene, Pd(PPh3)2, CuI, Et3N, dry DMF, 80 °C, 24 h, 62%; (e) TBAF, THF, r.t., 4 h, 83%; (f) H2, 10% Pd-C, r.t., 4 h, 90%; (g) BBr3, dry DCM, r.t., 4 h, 92%.

[0015] The compound 398 is prepared by the following reaction equation through a method comprising the following steps:

[0016]

[0017] Reagents and conditions: (a) Pd2(dba)3, t-BuOK, dry DMF, Ar, 80 °C, overnight, 81.4%; (b) ethyl triphenylphosphonium bromide, t-BuOK, THF, r.t., 6 h, 76.5%; (c) H2, Pd / C, r.t., 4 h, 89.5%; (d) BBr3, dry DCM, 2 h, 94.3%.

[0018] Another object of the present application is to provide the medical use of the compound of Formula I.

[0019] The medical use of the compound of Formula I provided by the present application is the use of the compound of Formula I in the preparation of a medicament having the function of any one of 1) to 4) below.

[0020] 1) inhibiting neuroinflammation,

[0021] 2) improving cognitive impairment,

[0022] 3) improving neurofunctional impairment,

[0023] 4) treating neurodegenerative diseases.

[0024] Specifically, the neuroinflammation can be LPS-induced neuroinflammation, and the neuroinflammation is inhibited by inhibiting the activation of microglia.

[0025] The cognitive impairment is the impairment of working memory, visual recognition memory and spatial memory ability caused by Aβ 1-42 .

[0026] The neurofunctional impairment can be Aβ 1-42 -induced neurofunctional impairment.

[0027] The neurodegenerative diseases include Alzheimer's disease.

[0028] Specifically, the use of the compound of Formula I as the only active ingredient in the preparation of the above medicament.

[0029] The present application also provides a medicament for treating neurodegenerative diseases, which contains the compound of Formula I.

[0030] Specifically, the medicament contains the compound of Formula I as the only active ingredient.

[0031] The present application has the following beneficial effects relative to the prior art: the present inventors first designed a new molecule generation model based on VAE, and designed and synthesized novel compounds 548 and 398 using this model. Through pharmacological experiments, it was found that compounds 548 and 398 both have the effect of inhibiting LPS-induced neuroinflammation, and in addition, novel compound 548 can improve neuroinflammation in LPS lateral ventricle injection mice, improve A 1-42 lateral ventricle injection mice, and thus the compound shown in formula I can be used to prepare a drug for treating Alzheimer's disease. BRIEF DESCRIPTION OF DRAWINGS

[0032] The accompanying drawings are included to provide a further understanding of the present application, and constitute a part of the specification, illustrate the present application together with the embodiments thereof, and explain the present application, but do not limit the present application. In the drawings:

[0033] Figure 1 Mass spectrum, H spectrum and C spectrum of compound 548 prepared in Example 1 of the present application.

[0034] Figure 2 Mass spectrum, H spectrum and C spectrum of compound 398 prepared in Example 2 of the present application.

[0035] Figure 3 Activation of microglial cells in the brain of mice during treatment with compound 548 in Example 3 of the present application. DETAILED DESCRIPTION

[0036] The preferred embodiments of the present application are described below in conjunction with the accompanying drawings, and it should be understood that the preferred embodiments described herein are only used to illustrate and explain the present application, and do not limit the present application.

[0037] The technical means used in the examples, if not specifically stated, are conventional means known to those skilled in the art, and the raw materials used are commercially available.

[0038] Example 1, comparison of predicted synthesizability of compounds 548 and 398

[0039] 1. Experimental protocol

[0040] 1.1. Drug design and screening process

[0041] The embodiments of the present application use the following design method:

[0042] The laboratory self-built anti-neuroinflammatory drug data is used as input data to construct an anti-inflammatory activity classification model. A series of compounds are designed using a new molecule generation model based on VAE and the anti-inflammatory activity classification model. The target compounds are selected by screening the novelty, synthesizability and drug activity of the newly generated compounds.

[0043] 1.2. Synthesis of compound 548

[0044] 548 Synthesis route and reaction conditions:

[0045]

[0046] Reagents and conditions: (a) NBS, AIBN, DCE, 80 °C, 8 h, 90%; (b) PPh3, CH3CH, reflux, 8 h, 89%; (c) anisaldehyde, LiOH, IPA, 60 °C, overnight, 75%; (d) trimethylsilyl acetylene, Pd(PPh3)2, CuI, Et3N, dry DMF, 80 °C, 24 h, 62%; (e) TBAF, THF, r.t., 4 h, 83%; (f) H2, 10% Pd-C, r.t., 4 h, 90%; (g) BBr3, dry DCM, r.t., 4 h, 92%.

[0047] A solution of 3,5-dibromo-4-methylanisole (5 g, 17.86 mmol, 1 eq) and N-bromosuccinimide (3.81 g, 21.43 mmol, 1.2 eq) in 50 mL of dichloroethane was added to azobisisobutyronitrile (0.59 g, 3.57 mmol, 0.2 eq). The mixture was stirred at 80 °C for 8 h until TLC monitoring showed that the reaction was complete. The solvent was quenched and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 (2 × 30 mL) solution and brine (2 × 20 mL). The organic phase was dried over MgSO4 and concentrated under vacuum. The resulting intermediate 1-1 (clear oil, 90% yield) was purified by flash column chromatography (silica gel, hexane). A solution of 1-1 (3 g, 8.43 mmol, 1 eq) and triphenylphosphine (4.42 g, 16.86 mmol, 2 eq) in 30 mL of acetonitrile was refluxed for 8 h. The solvent was then evaporated under reduced pressure, and the residue was dispersed in hexane and stirred for 2 h. The mixture was filtered under vacuum and dried for use in the next step without any purification. The intermediate was then dispersed in isopropanol with LiOH (0.4 g, 16.86 mmol, 2 eq) and anisaldehyde (1.38 g, 0.12 mmol, 1.2 eq), and the mixture was stirred at 80 °C for 12 h until TLC monitoring showed that the reaction was complete. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with brine (2 × 20 mL). The organic phase was dried on MgSO4 and concentrated under vacuum. The desired intermediate 1-2 was purified by flash column chromatography (silica gel, n-hexane:ethyl acetate = 8:1) (white, two-step yield 67%). Intermediates 1-2 (2 g, 5.05 mmol, 1 eq), trimethylsilylacetylene (0.6 g, 6.06 mmol, 1.2 eq), palladium dichloride bis(triphenylphosphine) (0.36 g, 0.51 mmol, 0.1 eq), cuprous iodide (0.29 g, 1.52 mmol, 0.3 eq), and triethylamine (1.02 g, 10.1 mmol, 2 eq) were dissolved in dry dimethylformamide under argon atmosphere. The mixture was stirred at 80 °C for 24 h until TLC monitoring showed that the reaction was complete. The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated under vacuum. The desired intermediates 1-3 (yellow oil, 62% yield) were purified by flash column chromatography (silica gel, n-hexane:ethyl acetate = 5:1). A solution of 1-3 (1.5 g, 3.47 mmol, 1 eq) in tetrahydrofuran was added dropwise with tetrabutylammonium fluoride (1.09 g, 4.16 mmol, 1.2 eq), and the mixture was stirred at room temperature for 4 h. The reaction was quenched with water and diluted with ethyl acetate. The organic phase was collected, dried over MgSO4, and concentrated under vacuum. The resulting intermediates 1-4 (yellow oil, 83% yield) were purified by flash column chromatography (silica gel, hexane:ethyl acetate = 6:1).To a solution of 1-4 (1 g, 3.47 mmol, 1 eq) in methanol, 10% palladium on carbon catalyst (0.4 g), the mixture was reacted at room temperature under hydrogen atmosphere until TLC monitoring showed the reaction was complete. The filtrate was collected and concentrated in vacuum. The resulting intermediate 1-5 (white solid, 90% yield) was purified by flash column chromatography (silica gel, n-hexane: ethyl acetate = 8: 1). A solution of 1-5 (1 g, 3.35 mmol, 1 eq) in dry dichloromethane, boron tribromide (1.68 g, 6.7 mmol, 2 eq) was added dropwise at 0 °C under argon, the mixture was stirred at room temperature for 4 h until TLC monitoring showed the reaction was complete. The reaction was quenched with water, extracted with ethyl acetate. The organic phase was collected, dried over MgS04and concentrated in vacuum. The resulting 548 (pale white solid, 92% yield) was purified by flash column chromatography (silica gel, hexane: ethyl acetate = 4: 1).

[0048] The mass spectrum, H spectrum and C spectrum of the resulting target product are shown in Figure 1 .

[0049] ESI-MS: 268.9 [M-H] +

[0050] 1 H NMR (600 MHz, DMSO-d6): 9.15 (s, 1H), 8.92 (s, 1H), 7.01-7.03 (m, 2H), 6.68-6.70 (m, 2H), 6.44 (m, 2H), 2.66-2.68 (m, 2H), 2.50-2.56 (m, 6H), 1.14 (t, J = 7.5 Hz, 6H).

[0051] 13 C NMR (150 MHz, DMSO-d6): 155.92, 155.72, 143.26, 132.62, 129.37, 127.61, 115.59, 113.30, 36.75, 30.75, 25.77, 16.07.

[0052] Confirmed as compound 548.

[0053] 1.3. Synthesis of compound 398

[0054]

[0055] Reagents and conditions: (a) Pd2(dba)3, t-BuOK, dried DMF, Ar, 80°C, overnight, 81.4%; (b) Ethyltriphenylphosphine bromide, t-BuOK, THF, rt, 6h, 76.5%; (c) H2, Pd / C, rt, 4h, 89.5%; (d) BBr3, dried DCM, 2h, 94.3%.

[0056] A solution of 2-bromo-4-methoxybenzaldehyde (3 g, 14.02 mmol, 1 eq), 4-methoxystyrene (2.26 g, 16.82 mmol, 1.2 eq), tris(dibenzylacetone)dipalladium (2.56 g, 2.80 mmol, 0.2 eq), and potassium tert-butoxide (3.15 g, 28.04 mmol, 2 eq) in dry dimethylformamide was prepared. The mixture was stirred at 80 °C under argon atmosphere for 20 h until TLC monitoring showed that the reaction was complete. The reactants were diluted with water and extracted with ethyl acetate. The organic phase was collected, dried on MgSO4, and concentrated under vacuum. The resulting intermediate 2-1 (white solid, 81.4% yield) was purified by flash column chromatography (silica gel, n-hexane:ethyl acetate = 8:1). A solution of 2-1 (2 g, 7.46 mmol, 1 eq), ethyltriphenylphosphonium bromide (3.32 g, 8.95 mmol, 1.2 eq), and potassium tert-butoxide (1.67 g, 14.92 mmol, 2 eq) in tetrahydrofuran was added. The mixture was stirred at room temperature under argon for 6 h until TLC monitoring showed the reaction was complete. The reactants were diluted with water and extracted with ethyl acetate. The organic phase was collected, dried on MgSO4, and concentrated under vacuum. The resulting intermediate 2-2 (white solid, 76.5% yield) was purified by flash column chromatography (silica gel, hexane:ethyl acetate = 6:1). A solution of 2-2 (1 g, 3.57 mmol, 1 eq) in methanol and 10% palladium on carbon catalyst (0.4 g) were added, and the mixture was reacted at room temperature under hydrogen until TLC monitoring showed the reaction was complete. The filtrate was collected and concentrated under vacuum. The obtained intermediate 2-3 (white solid, 89.5% yield) was purified by flash column chromatography (silica gel, hexane: ethyl acetate = 6:1). A solution of 2-3 (1 g, 3.52 mmol, 1 eq) in dry dichloromethane was added dropwise to boron tribromide (1.76 g, 7.04 mmol, 2 eq) at 0 °C under argon atmosphere. The mixture was stirred at room temperature for 2 h until TLC monitoring showed that the reaction was complete. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was collected, dried on MgSO4, and concentrated under vacuum. The obtained 398 (pale white solid, 94.3% yield) was purified by flash column chromatography (silica gel, hexane: ethyl acetate = 5:1).

[0057] The mass spectra, H-s spectra, and C-s spectra of the obtained products are shown in [reference needed]. Figure 2.

[0058] ESI-MS: 257.1 [M+H] + , 279.1 [M+Na] + , 254.3 [M-H] + ;

[0059] 1 H NMR (600 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.99 (s, 1H), 7.00-7.02 (m, 2H), 6.90-6.91 (m, 1H), 6.67-6.68 (m, 2H), 6.59 (m, 1H), 6.51-6.53 (m, 1H), 2.65-2.70 (m, 4H), 2.42-2.45 (m, 2H), 1.48 (dd, J = 15.2, 7.5 Hz, 1H), 0.90 (t, J = 7.3 Hz, 1H).

[0060] 13 C NMR (150 MHz, DMSO-d6) δ 155.89, 155.66, 140.82, 132.31, 130.45, 130.33, 129.53, 116.14, 115.52, 113.27, 36.67, 35.17, 33.83, 24.61, 14.47.

[0061] Confirmed as compound 398.

[0062] 2. Experimental results

[0063] 2.1. Synthesizability prediction of compounds 548 and 398

[0064] The synthesizability of compounds 548 and 398 was predicted by using the computational model. As shown in Table 1, both 548 and 398 have a low SA score of 2.20 and 1.98, respectively, which indicates that compounds 548 and 398 are relatively easy to synthesize.

[0065] Table 1. Synthesizability prediction

[0066]

[0067] 3. Conclusion

[0068] The above results show that the new compounds 548 and 398 designed by the new molecule generation model based on VAE are relatively easy to synthesize.

[0069] Example 2, Study on Anti-neuroinflammatory effect of new compounds

[0070] 1. Experimental grouping and scheme

[0071] The well 3-8 generation BV2 cells were plated in 96-well plates and incubated in 37°C incubator. After 24h, the cells were treated with drugs, and blank control group, LPS (100 ng / ml) treatment group and LPS (100 ng / ml) plus different concentrations of drug groups were set up. After 24h of drug treatment, 50 μL supernatant was taken and added to a new 96-well plate, and 50 μL Griess solution was added, and the plate was incubated in 37°C incubator for 10 min. The absorbance was detected at 540 nm. After 24h of drug treatment, 10 μL MTT detection solution was added to each well of the 96-well plate, and the plate was incubated in 37°C incubator for 4h, and then the culture medium was discarded and 150 μL DMSO was added to dissolve the formazan. The absorbance was detected at 490 nm by a microplate reader.

[0072] 2. Experimental results

[0073] 2.1. Compounds 548 and 398 can significantly inhibit neuroinflammation

[0074] The anti-inflammatory effects of compounds 548 and 398 were detected by Griess experiment, as shown in Table 2, both compounds 548 and 398 can significantly inhibit the production of NO in BV2 cells induced by LPS, and the inhibitory effect of 548 is the best. The cytotoxicity of 548 and 398 was evaluated by MTT experiment, as shown in Table 3, 1 μM and 10 μM of 548 and 398 did not inhibit the cell viability of BV2 cells.

[0075] Table 2. Effect of compounds on NO content (%)

[0076]

[0077] Table 3. Effect of compounds on cell survival rate (%) of BV2 cells (mean ± SEM)

[0078]

[0079] 3. Conclusion

[0080] The above results show that both compounds 548 and 398 can significantly inhibit LPS-induced neuroinflammation, and low concentration of compounds does not produce cytotoxicity, and the activity of 548 is the best.

[0081] Example 3, Study on the Anti-neuroinflammatory Effect of Compound 548

[0082] 1. Experimental grouping and scheme

[0083] C57BL / 6 mice were randomly divided into 5 groups: sham operation group, LPS group and different concentrations of drug treatment group (1 mg / kg, 2.5 mg / kg, 5 mg / kg). And respectively by gavage CMC-Na or different concentrations of drug. After a week of administration, LPS group of mice and drug treatment group of mice were LPS lateral ventricle injection experiment. The mice were anesthetized with tri- bromoethanol and fixed on a stereotaxic apparatus, and the iodine was wiped off the mouse head hair after taking the iodine, and the scalp was cut to expose the skull, and the positioning instrument was adjusted to the bregma point and taken as the zero point. Adjust the coordinates to x = 1.2, y = -0.6, z = 2.2, slowly inject LPS. After injection, the mouse head skin was sutured. 24 h later, the mouse brain was taken for subsequent study.

[0084] The mouse brain was completely stripped and fixed in 4% paraformaldehyde for 24 h, and incubated in 20% sucrose solution and 30% sucrose solution respectively for 24 h. After incubation, the tissue was stored in a-80℃ refrigerator. At the beginning of the frozen section, the tissue was fixed on the microtome, each brain tissue was cut 10 nm, and then respectively antigen repair, 3% goat serum fixation, Iba-1 antibody incubation overnight and fluorescence secondary antibody incubation were carried out, and then photographed under fluorescence microscope.

[0085] 2. Experimental results

[0086] 2.1. Compound 548 inhibits microglial cell activation

[0087] By detecting the effect of compound 548 on the number of Iba-1 positive cells in the brain of mice after LPS stimulation, the anti-inflammatory effect of compound 548 was evaluated. As shown in Figure 3 Compound 548 can significantly inhibit the number of Iba-1 positive cells in the brain of mice, which indicates that compound 548 can inhibit the activation of microglial cells and inhibit neuroinflammation.

[0088] 3. Conclusion

[0089] The above results show that compound 548 can inhibit the abnormal activation of mouse microglial cells caused by LPS and inhibit neuroinflammation.

[0090] Example 4, compound 548 improves Aβ 1-42 cognitive impairment of mice

[0091] C57BL / 6 mice were randomly divided into 6 groups: sham operation group, Aβ 1-42Group, different concentrations of drug treatment group (1 mg / kg, 2.5 mg / kg, 5 mg / kg) and positive drug group. And respectively by gavage CMC-Na or different concentrations of drugs. Five days after administration, the mice were injected into the lateral ventricle, and the specific experimental process was similar to that of Example 3. The behavior experiment started one week after the lateral ventricle injection, including Y maze experiment, novel object discrimination experiment and Morris water maze experiment to evaluate the cognitive ability of mice.

[0092] 2. Experimental results

[0093] 2.1. Compound 548 improves the Aβ 1-42 Working memory ability of mice

[0094] The Y maze experiment was used to detect the effect of compound 548 on the Aβ 1-42 Working memory ability of mice. As shown in Table 4, there was no significant difference in the total arm entry times of each group; the mice after Aβ 1-42 The spontaneous alternation rate was significantly reduced after lateral ventricle injection. High-dose compound 548 can reverse this change. It shows that compound 548 can improve the Aβ 1-42 Working memory ability of mice.

[0095] Table 4. Effect of 548 on Aβ 1-42 Working memory ability of mice (mean ± SEM)

[0096]

[0097]

[0098] 2.2, Compound 548 improves the Aβ 1-42 Visual recognition memory ability of mice

[0099] The novel object discrimination experiment was used to detect the effect of compound 548 on the Aβ 1-42 Visual recognition memory ability of mice. As shown in Table 5, there was no significant difference in the total object exploration time of each group; the mice after Aβ 1-42 The discrimination index was significantly reduced after lateral ventricle injection. Medium-dose and high-dose compound 548 can reverse this change. It shows that compound 548 can improve the Aβ 1-42 Visual recognition memory ability of mice.

[0100] Table 5. Effect of 548 on Aβ 1-42 Visual recognition memory ability of mice (mean ± SEM)

[0101]

[0102] 2.3, Compound 548 improves the Aβ 1-42 Spatial memory ability of mice

[0103] The Morris water maze test was used to detect the effect of compound 548 on Aβ 1-42 The average swimming speed of each group was not significantly different. As shown in Table 6, the time spent in the target quadrant, the swimming distance in the target quadrant and the number of crossing the platform were significantly reduced after the lateral ventricle injection of Aβ 1-42 Compound 548 at high dose can reverse these changes. It is shown that compound 548 can improve the working memory, the spatial memory and the cognitive impairment of mice caused by Aβ 1-42 The spatial memory ability of mice.

[0104] Table 6. The effect of compound 548 on Aβ 1-42 The spatial memory ability of mice.

[0105]

[0106]

[0107] 3. Conclusion

[0108] The above results show that compound 548 can improve the working memory, the spatial memory and the cognitive impairment of mice caused by Aβ 1-42 Compound 548 can improve the working memory, the spatial memory and the cognitive impairment of mice caused by Aβ 1-42 The cognitive impairment of mice.

[0109] Obviously, those skilled in the art can make various modifications and variations to the present application without departing from the spirit and scope of the present application. Thus, if these modifications and variations of the present application belong to the scope of the claims of the present application and their equivalents, the present application also intends to include these modifications and variations.

Claims

1. Any one of the following compounds: 。 2. Use of the compound of claim 1 for the manufacture of a medicament having any one of the following functions 1) - 4): 1) inhibiting neuroinflammation, 2) ameliorating cognitive impairment, 3) ameliorating neurofunctional impairment, 4) treating neurodegenerative disease.

3. Use according to claim 2, wherein: The neuroinflammation is LPS-induced neuroinflammation.

4. The use according to claim 2, characterized in that: The cognitive disorder is Aβ 1-42 causing impairment of working memory, visuospatial recognition memory, and spatial memory abilities.

5. The use according to claim 2, wherein: The neurological impairment is Aβ 1-42 Induced neurological impairment.

6. The use according to claim 2, characterized in that: The neurodegenerative disease includes Alzheimer's disease.

7. A medicament for treating neurodegenerative disease, comprising the compound of claim 1.

8. The medicament according to claim 7, characterized in that: The medicament has the compound of claim 1 as the only active ingredient.

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